Multiple myeloma is a plasma cell neoplasm with poor prognosis but promising future treatment. Current measurements of myeloma disease burden are suboptimal, and this limits clinical care. We have completed a first-in-human trial of CD38-targeted immunoPET with the radiolabeled anti-CD38 monoclonal antibody, 89Zr- DFO-daratumumab, which very successfully visualized myeloma disease burden as never done before. This proposal is a phase 2 clinical trial to identify clinically valuable applications of CD38-targeted immunoPET in patients with multiple myeloma. Our central hypothesis is that targeted imaging of CD38, which is expressed on the surface of virtually every myeloma cell, will allow clinically valuable non-invasive immuno-PET imaging of patients with myeloma. This would be a transformative strategy for the measurement of myeloma tumor burden, selection of therapeutic agents, and monitoring of treatment response. In the first aim of the study, we will determine the correlation between tumor uptake of 89Zr-DFO-daratumumab with clinically standard laboratory and imaging measurement of myeloma, including patient serum M protein concentration, percentage of plasma cells on bone marrow biopsy, FDG PET/CT, and whole-body MR. Because current approaches to assessing myeloma tumor burden are sub-optimal, developing a method to sensitively visualize and localize myeloma could have a profound impact on patient care. In the second aim of the study, we will determine if tumor uptake of 89Zr-DFO-daratumumab predicts response to daratumumab-containing combination therapy. Not all patients respond to daratumumab therapy; thus, a method of predicting response would be valuable for selection of therapy in individual patients. In the third aim, we will determine if 89Zr-DFO-daratumumab imaging following daratumumab-containing combination therapy can detect clinically significant residual disease. Detection of minimal residual disease (MRD) following therapy continues to grow in importance as a prognostic marker and endpoint in myeloma clinical trials. A method of visualizing and localizing residual disease would impact patient care, as well as enhance trials of developing myeloma therapies. The ultimate goal of this work would be the identification of clinically valuable applications for 89Zr-DFO- daratumumab immunoPET and, if successful, advancement toward FDA approval of this agent.